eStressMap

Harnessing innate immunity to improve human health

The Center for Innate Immunity and Immune Disease (CIIID) is a scientific research center based at the University of Washington School of Medicine in Seattle, where researchers from diverse scientific backgrounds work together and focus their expertise to discover how innate immunity dictates the body’s response to infectious disease or impacts autoimmune disease. CIIID scientists have access to four world class service cores with specific expertise in innate immunity: Human Cell Signaling, Transgenic Mouse Core, Immuno-informatics & Computational Modeling Core, and Translation Core. The CIIID also features an Education Core that hosts multiple programs for middle and high school students to conduct research in innate immunity. For additional information about CIIID and what we do, visit our website at ciiid.washington.edu or email us at CIIID@uw.edu

ATIMODIS

Integrated Modeling of Social Interactions as function of environmental and genetic dynamics. The project will contribute to a better understanding of universals involved in such processes as the spreading of epidemics, human migrations, territorial dynamics and ethno-cultural genesis. An ambitious modelling of the relations between cultural norms, practices and demographical environment might result in benefits for the guidance of policies related to ecology and human development.

Dimensionality Reduction, Innate Structure

'Omics' data have increased very rapidly in quantity and resolution, and are increasingly recognized as very valuable experimental observations in the systematic study of biological phenomena. The increase in availability, complexity and nonexpert interest in such data requires the urgent development of accurate and efficient dimensionality reduction and visualization techniques. We recently developed a unique blend of linear and non-linear dimensionality reduction techniques and stochastic simulations to overcome some of the present limitations of dimensionality reduction.

Systems Immunology and Genetics of Infectious Disease

The Indo-French associated international laboratory on "Systems Immunology and Genetics of Infectious Disease" (LIA SIGID) has been created on November 14th, 2012 by the French CNRS and the Indian DBT to foster close collaboration between multidisciplinary teams in India and France including clinicians, immunologists, geneticists, molecular biologists, and mathematicians. The LIA SIGID is dedicated to the study of the most prevalent infectious diseases in India affecting millions of individuals per year. The systems epigenomics laboratory is one of the three French founder laboratories.

Analysis of Complex Combinatorial Enhancers

The question of how to integrate heterogeneous sources of biological information into a coherent framework that allows the gene regulatory code in eukaryotes to be systematically investigated is one of the major challenges faced by systems biology. Probability landscapes, which include as reference set the probabilistic representation of the genomic sequence, have been proposed as a possible approach to the systematic discovery and analysis of correlations amongst initially heterogeneous and un-relatable descriptions and genome-wide measurements. Much of the available experimental sequence and genome activity information is de facto, but not necessarily obviously, context dependent. Furthermore, the context dependency of the relevant information is itself dependent on the biological question addressed. It is hence necessary to develop a systematic way of discovering the context-dependency of functional genomics information in a flexible, question-dependent manner.
We have demonstrated how feature context-dependency can be systematically investigated using probability landscapes. Furthermore, we show how different feature probability profiles can be conditionally collapsed to reduce the computational and formal, mathematical complexity of probability landscapes. Interestingly, the possibility of complexity reduction can be linked directly to the analysis of context-dependency. The formal structure proposed contributes to a concrete and tangible basis for attempting to formulate novel mathematical structures for describing gene regulation in eukaryotes on a genome-wide scale.

Epigenomic Regulation by Thymine-DNA Glycosylase Complexes

The thymine DNA glycosylase (TDG) is a multifunctional enzyme, which is essential for embryonic development. It mediates the base excision repair (BER) of G:T and G:U DNA mismatches arising from the deamination of 5-methyl cytosine (5-MeC) and cytosine, respectively. Recent studies have pointed at a role of TDG during the active demethylation of 5-MeC within CpG islands. TDG interacts with the histone acetylase CREB-binding protein (CBP) to activate CBP-dependent transcription. In addition, TDG also interacts with the retinoic acid receptors (RARs), resulting in the activation of RAR target genes. We recently provided evidence for the existence of a functional ternary complex containing TDG, CBP and activated RAR. Using global transcriptome profiling, we uncovered a coupling of de novo methylation-sensitive and RA-dependent transcription, which coincides with a significant subset of CBP target genes. The introduction of a point mutation in TDG, which neither affects overall protein structure nor BER activity, leads to a significant loss in ternary complex stability, resulting in the deregulation of RA targets involved in cellular networks associated with DNA replication, recombination and repair. We thus demonstrate for the first time a direct coupling of TDG's epigenomic and transcription regulatory function through ternary complexes with CBP and RAR.

eStressMap

We address for the first time the molecular and cellular roles of chronic environmental stress in two debilitating and prevalent age-related neurodegenerative disorders, Alzheimer´s and Parkinson diseases (AD and PD, respectively). This effort addresses the role of stress as an important and common underlying culprit in these diseases. The consortium is comprised of leading experts who are basic scientists and neurologists working together in the field of stress and HPA axis physiology (hypothalamic-pituitary-adrenal axis - the principle effector system of stress), AD and PD pathologies.

NEUROM

Computational Modeling of Human Brain Metabolism and Immune Activation triggering the Onset of Rare and Common Demyelinating Disease. Joint project with the laboratory of Aurora Pujol-Onofre, M.D. Ph.D. from the IDIBELL in Barcelona, Spain.

7SK snRNA

The small nuclear 7SK RNA negatively controls transcription by inactivating positive transcription elongation factor b (P-TEFb) and is an integral component of Tat-dependent and independent HIV-1 transcription initiation complexes. We have recently shown that 7SK RNA also directly controls HMGA1 transcription activity through direct binding. HMGA1 is a master regulator of gene expression and its deregulation is associated with virtually any type of human cancer. The degree of HMGA1 over-expression thereby correlates with tumor malignancy and metastatic potential. We succeeded in identifying and characterizing HMGA1-dependent and independent effects of 7SK snRNA. CTIP2 represses P-TEFb activity in a complex containing 7SK RNA and HEXIM1. Recently, the inactive 7SK/P-TEFb small nuclear RNP (snRNP) has been detected at the HIV-1 core promoter as well as at the promoters of cellular genes, but a recruiting mechanism still remains unknown to date. We have shown global synergy between CTIP2 and HMGA1 in terms of P-TEFb-dependent endogenous and HIV-1 gene expression regulation. Our findings not only provide insights into a recruiting mechanism for the inactive 7SK/P-TEFb snRNP, but may also contribute to a better understanding of viral latency. Òp>

Feb 2015: LIA SIGID Inauguration

Systems Immunology and Genetics of Infectious Disease. France-India International Laboratory.

The opening symposium and the biennial steering committee meeting of the International Laboratory SIGID "Systems Immunology and Genetics of Infectious Diseases" will take place at the Institut Pasteur de Lille, France on February 5-6, 2015.

Streptococcus pneumoniae (pneumococcus) is the main etiological agent of human pneumonia and meningitis, otitis media and sinusitis; per year, about 1-2 million of fatal pneumococcal diseases occur worldwide. In the context of a previous EU-funded collaboration between our groups in France and Uruguay, we established an experimental model of invasive infection with a clinical isolate of S. pneumoniae serotype 1 together with a model of protective immunity against lethal challenge with the pathogen.
We apply geometric pattern recognition and multi-parametric, multi-objective (MPMO) optimization techniques to decipher the mechanisms of the host-pathogen interaction in this diesease model. Taken together with similarly innovative technology to infer targets and target networks from the host’s gene expression profiles allows us to stratify the bench-to-bedside path by repurposing existing drugs with unprecedented speed, accuracy, and functional annotation including possible off-target effects.

Over the course of cortical neurogenesis, the transition of progenitors from proliferation to differentia- tion requires a precise regulation of involved gene networks under varying environmental conditions. In order to identify such regulatory mechanisms, we analyzed microRNA (miRNA) target networks in progenitors during early and late stages of neuro- genesis. We found that cyclin D1 is a network hub whose expression is miRNA-dosage sensitive. Experimental validation revealed a feedback regula- tion between cyclin D1 and its regulating miRNAs miR-20a, miR-20b, and miR-23a. Cyclin D1 induces expression of miR-20a and miR-20b, whereas it represses miR-23a. Inhibition of any of these miRNAs increases the developmental stage-specific mean and dynamic expression range (variance) of cyclin D1 protein in progenitors, leading to reduced neuronal differentiation. Thus, miRNAs establish robustness and stage-specific adaptability to a critical dosage-sensitive gene network during cortical neurogenesis. Understanding such network regulatory mechanisms for key developmental events can provide insights into individual suscepti- bilities for genetically complex neuropsychiatric disorders.

Systems Epigenomics and Alternative Splicing. TAF6delta

The TAF6d pathway of apoptosis can dictate life versus death decisions independently of the status of p53 tumor suppressor. TAF6d is an inducible pro-apoptotic subunit of the general RNA polymerase II (Pol II) transcription factor TFIID. Alternative splice site choice of TAF6d has been shown to be a pivotal event in triggering death via the TAF6d pathway, yet nothing is currently known about the mechanisms that promote TAF6d splicing. Furthermore the transcriptome impact of the gain of function of TAF6d versus the loss of function of the major TAF6a splice form remains undefined. Here we employ comparative microarray analysis to show that TAF6d drives a transcriptome profile distinct from that resulting from depletion of TAF6a. To define the cis-acting RNA elements responsible for TAF6d alternative splicing we performed a mutational analysis of a TAF6 minigene system. The data point to several new RNA elements that can modulate TAF6d and also reveal a role for RNA secondary structure in the selection of TAF6d.

Systems Epigenomics Laboratory.

Principle Investigator

Dr. Benecke is a tenured researcher with the French Centre National de la Recherche Scientifique (CNRS, tenure was obtained in 2003) and has strong expertise in biochemistry and mathematics / bioinformatics of gene expression regulation in higher eukaryotes in the context of host-pathogen interactions and immune responses as well as neurobiology. He is an author of over 90 papers, reviewed conference proceedings and reviews, about half of which are related to transcriptional regulation and functional genomics the other half being related to novel computational and geometric analysis, representation, and inference strategies. Several of his contributions to high-throughput data analysis in the context of functional genomics have set new standards for array, next-generation sequencing, proteome and metabolome profiling and integration approaches. He is used to directing a group of experimental biochemists and molecular biologists as well as theoreticians and computer scientists, and has experience in managing multi-site collaborative research endeavours. Dr. Benecke has received independent research funding from national, European, and international funding agencies and collaborated in two N.I.H./N.I.A.I.D. funded projects. From 2005 to 2010 Dr. Benecke was one of four CNRS scientists to be entrusted with the design and construction of the Interdisciplinary Research Institute in Lille, now a recognized CNRS laboratory. From 2007 to 2012 Dr. Benecke headed the French non-human primate bioinformatics core of the Agence Nationale de Recherches sur le SIDA et les Hepatites Virales (ANRS, the French national AIDS and Hepatitis research organization). Since 2002 Dr. Benecke is affiliated withthe Institut des Hautes Etudes Scientifiques (IHES, a hors-pair private research institute in mathematics). In 2003 Dr. Benecke has been recognized with the prestigious European Hematology Association -- Jose Carreras Foundation Young
Investigator Award. He has recently returned from a sabbatical at the University of Washington, Seattle, U.S.A. and moved to the University Pierre and Marie Curie (UPMC, ranked no.1 in France). His current research focusses on using systems, computational, and synthetic biology to develop new gene regulatory network inference technologies for the study of biochemical and signaling networks in infectious disease and neuropsychiatric disorders. He is particularly interested in uncovering and exploring links between the infectious history during gestation and early life and resulting neuro-developmental disorders.

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Acknowledgements

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